PROJECT SUMMARY Both alcoholic and non-alcoholic fatty liver diseases (AFLD and NAFLD, respectively) cause serious health problems in the US. AFLD occurs in nearly all excessive alcohol drinkers and NAFLD afflicts approximately one-third of adult population. Worse yet, there is no effective treatment for either AFLD or NAFLD at this time. In this proposed research, we plan to investigate molecular mechanisms of Sestrin3 (Sesn3) in the regulation of hepatic lipid metabolism. There are two specific aims in this project. Aim# 1 is to determine the protective mechanism of Sesn3 against AFLD and NAFLD through the Atg14-regulated autophagy pathway. Aim #2 is to examine the role of Sesn3-mTORC2 pathway in the pathogenesis of AFLD and NAFLD. It is anticipated that the findings from this proposed research should provide valuable information for therapeutic development to treat AFLD and NAFLD.